This Program Project Grant application describes studies we plan to perform as a continuation of our[unreadable] previous projects concerned with the regulation of cardiovascular function, primarily by endothelium-derived[unreadable] mediators, nitric oxide and reactive oxygen species. The present application builds on our previously[unreadable] obtained data to further establish the role of these agents in the control of vascular and cardiac function. Our[unreadable] overall hypothesis that we aim to test is that oxygen radical species, derived through activation of Nox[unreadable] oxidases in the vessel wall, by causing a reduction in nitric oxide bioavailability, hasten the development of[unreadable] vascular dysfunction leading to disease. In the first Project, Dr. Wolin will characterize how Nox-linked signaling[unreadable] mechanisms affect vascular function and how these mechanisms are altered in pathophysiologic conditions.[unreadable] In the second Project, Dr. Hintze will examine in mice, rats and dogs the role of NADPH oxidase in the increased[unreadable] oxidant production secondary to sodium restriction, a state associated with increased angiotensin[unreadable] production. He will also determine in the dog heart the effects of sodium restriction on NO dependent[unreadable] regulation of the coronary circulation as well as the fate of substrates and the alteration in the expression of[unreadable] metabolic enzymes. In the third Project, Dr. Kaley plans to study the effects of aging on vascular function in type 2[unreadable] diabetic (db/db) and eNOS-KO mice, two different models of metabolic syndrome, each of which is[unreadable] characterized by increased oxidant stress and a reduction in nitric oxide bioavailability. The projects will be[unreadable] supported by three cores; one led by Dr. Edwards, providing genotyping of and physiologic measurements in[unreadable] mice, one led by Dr. Ungvari who will provide expertise in imaging ROS in vessels and tissues by state of the[unreadable] art methods and one led by Dr. Ojaimi, who will interpret data obtained by gene array techniques. We[unreadable] believe that our research will provide conceptual advances that will likely lead to a better understanding of[unreadable] the development of vascular dysfunction in disease states as well as to novel therapeutic options.[unreadable]